N-(3-Aminopropyl)-N-phenyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide derivatives, their preparation and their therapeutic use

ABSTRACT

Compounds of the formula: ##STR1## in which R 1  represents a hydrogen or halogen atom or a methyl or C 1  -C 4  alkoxy group, R&#39; 1  represents a hydrogen or halogen atom, R&#34; 1  represents a hydrogen atom or a methoxy group, R 3  represents a C 1  -C 3  alkyl group, R 4  represents a 2,3-dihydro-1H-inden-2-yl, 2,3-dihydro-1H-inden-1-yl or 1,2,3,4-tetrahydronaphthalen-1-yl group, or R 3  and R 4  together form, with the adjacent nitrogen atom, a 1,2,3,4-tetrahydroisoquinol-2-yl, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl, 5,8-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-yl, 1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-3-yl, 4,5,6,7-tetrahydrothieno[2,3-c]pyrid-6-yl, 2,3-dihydro-1H-isoindol-2-yl or 2,3,4,5-tetra-hydro-1H-3-benzazepin-3-yl, group are useful in the treatment of cerebral disorders.

This is a continuation of application Ser. No. 08/382,578, filed Feb. 2,1995, now U.S. Pat. No. 5,550,162.

The present invention relates toN-(3-aminopropyl)-N-phenyl-5,6,7,8-tetrahydronaphthalene-2-carboxamidederivatives, to their preparation and to their therapeutic use.

The invention provides the compounds of the general formula (I) ##STR2##in which R₁ represents a hydrogen or halogen atom, a methyl group or aC₁ -C₄ alkoxy group,

R'₁ represents a hydrogen or halogen atom,

R"₁ represents a hydrogen atom or a methoxy group,

R₃, taken alone, represents a C₁ -C₃ alkyl group,

R₄, taken alone, represents a 2,3-dihydro-1H-inden-2-yl group, a2,3-dihydro-1H-inden-1-yl group or a 1,2,3,4-tetrahydronaphthalen-1-ylgroup, or alternatively

R₃ and R₄ together form, with the nitrogen atom to which they areattached, a 1,2,3,4-tetrahydroisoquinol-2-yl group, a6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl group, a5,8-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl group, a1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-yl group, a1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-3-yl group, a4,5,6,7-tetrahydrothieno[2,3-c]pyrid-6-yl group, a2,3-dihydro-1H-isoindol-2-yl group or a2,3,4,5-tetra-hydro-1H-3-benzazepin-3-yl group, the respective formulaeof which are as follows: ##STR3## provided that, when R₁ is alkoxy andeach of R'₁ and R"₁ is hydrogen, R₃ and R₄ do not form, with thenitrogen atom, an unsubstituted or substituted tetrahydroisoquinol-2-ylgroup.

Preferred compounds of the invention, are those in whose formula R₁represents a halogen atom, R'₁ represents a hydrogen or halogen atom,R"₁ represents a hydrogen atom, R₃, taken alone, represents a C₁ -C₃alkyl group, R₄, taken alone, represents a 2,3-dihydro-1H-inden-2-ylgroup, a 2,3-dihydro-1H-inden-1-yl group or a1,2,3,4-tetrahydro-naphthalen-1-yl group, or alternatively R₃ and R₄together form, with the nitrogen atom to which they are attached, a1,2,3,4-tetrahydroisoquinol-2-yl group, a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl group or a5,8-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl group.

Among these preferred compounds, the most advantageous areN-[3-[(2,3-dihydro-1H-inden-2-yl)methylamino]propyl]-N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide,N-[3-[(2,3-dihydro-1H-inden-1-yl)methylamino]propyl]-N-(3,4,dichlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide,andN-[3-[(1,2,3,4-tetrahydronaphthalen-1-yl)methylamino]propyl]-N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide.

The compounds of the invention may exist in the form of bases or acidaddition salts.

Moreover, when R₄ contains an asymmetric carbon atom, that is to saywhen R₄ represents a 2,3-dihydro-1H-inden-1-yl group or a1,2,3,4-tetrahydronaphthalen-1-yl group, the compounds may exist in theform of pure optical isomers or mixtures of such isomers.

According to a feature of the invention, the compounds of formula (I)are prepared according to a process illustrated by the followingreaction scheme: ##STR4##

A benzenamine of general formula (II), in which R₁, R'₁ and R"₁ are asdefined above, is reacted with methyl5,6,7,8-tetrahydronaphthalene-2-carboxylate of formula (III), forexample in the presence of sodium hydride and in a solvent such asdimethyl sulphoxide. An amide of general formula (IV) is obtained, whichis then reacted with 1-bromo-3-chloro-propane of formula (V), forexample in the presence of sodium hydride and in a solvent such asN,N-dimethyl-formamide.

A chloro derivative of general formula (VI) is obtained, which isfinally reacted with an amine of general formula HNR₃ R₄, in which R₃and R₄ are as defined above, for example in the presence of potassiumiodide and of a base such as potassium carbonate, in a solvent such asN,N-dimethylformamide.

The benzenamines of general formula (II) are commercially available, aredescribed in the literature, for example in European Patent ApplicationsEP-A-0,144,730 and EP-A-0,300,865, or are available by methods describedin the literature or known to those skilled in the art.

Methyl 5,6,7,8-tetrahydronaphthalene-2-carboxylate is described in J.Amer. Chem. Soc. (1943) 65 1097.

The amines of general formula (VII), in which R₄ represents a2,3-dihydro-1H-inden-2-yl group, are described in J. Med. Chem. (1980)23 745.

The amines of general formula (VII), in which R₄ represents a2,3-dihydro-1H-inden-1-yl group, are described in J. Amer. Chem. Soc.(1966) 88 2233.

The amines of general formula (VII), in which R₄ represents a1,2,3,4-tetrahydronaphthalen-1-yl group, are described in J. Amer. Chem.Soc. (1960) 82 459, in C. R. Hebd. Seances Acad. Sci. Ser. C. (1969) 2682225 and in J. Med. Chem. (1966) 9 830.

The 1,2,3,4-tetrahydroisoquinol-2-yl derivatives corresponding to thegeneral formula (VII) are commercially available or are described in theliterature.

The 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole corresponding to thegeneral formula (VII) is described in Organic Synthesis (1971) 56 136.

The 1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indole corresponding to thegeneral formula (VII) is described in J. Chem. Soc. (1968) 1235.

The 4,5,6,7-tetrahydrothieno[2,3-c]pyridine corresponding to the generalformula (VII) is described in Arkiv. Kemi (1970) 13(19) 217.

The 2,3,-dihydro-1H-isoindole corresponding to the general formula (VII)is described in Organic Synthesis Coll. (1973) 5 406.

The 2,3,4,5-tetrahydro-1H-3-benzazepine corresponding to the generalformula (VII) is described in Helv. Chim. Acta (1935) 18 1388.

The Examples which follow illustrate in detail the preparation ofcompounds according to the invention. The elemental microanalyses andthe I.R. and N.M.R. spectra confirm the structures of the compoundsobtained. The numbers indicated in parentheses in the example titlescorrespond to those in the 1st column of the Table given later.

EXAMPLE 1

(Compound No. 2)

N-[3-[(2,3-dihydro-1H-inden-2-yl)methylamino]propyl]-N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamideethanedioate (1:1) and (E)-2-butenedioate (1:1)

1.1. N-(3,4-Dichlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide.

To a suspension of 1.008 g (0.021 mol) of sodium hydride (50% in oil) in8 ml of dimethyl sulphoxide, under an argon atmosphere, is added onedrop of methanol. The mixture is left to stir for 10 min., and 1.94 g(0.012 mol) of 3,4-dichloro-benzenamine are added. The mixture isstirred for 15 min, 2.0 g (0.0105 mol) of methyl5,6,7,8-tetrahydro-naphthalene-2-carboxylate dissolved in 8 ml ofdimethyl sulphoxide are added dropwise, and the stirring is continued atroom temperature for 3 h. 150 ml of water, 50 ml of diethyl ether, and50 ml of ethyl acetate are added slowly, and the organic phase isseparated, washed successively with 50 ml of water and 50 ml ofsaturated aqueous sodium chloride solution, dried over magnesiumsulphate and filtered. The solvent is evaporated. The residue iscrystallized from a mixture of diethyl ether and hexane, and 2.09 g ofproduct are obtained, which is used as it is in the following step.

1.2.N-(3-Chloropropyl)-N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide.

To a solution of 2.05 g (0.0064 mol) ofN-(3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide in 11ml of N,N-dimethylformamide, under a nitrogen atmosphere, is addedslowly, in small portions, 0.369 g (0.0077 mol) of sodium hydride as a50% suspension in oil. The mixture is cooled to 0° C. 1.26 g (0.008 mol)of 1-bromo-3-chloropropane are added dropwise. The mixture is allowed toreturn to room temperature and stirring is continued for 4 h.

The mixture is cooled, 50 ml of water and 50 ml of diethyl ether areadded slowly, the phases are separated and the aqueous phase isextracted with 50 ml of diethyl ether. The organic phases are combinedand are washed successively with twice 50 ml of water, with 50 ml of 1Nhydrochloric acid, with twice 50 ml of water and with 50 ml of saturatedaqueous sodium chloride solution, dried over magnesium sulphate and thesolvent is evaporated. 2.51 g of product are obtained, which is used asit is in the following step.

1.3.N-[3-[(2,3-Dihydro-1H-inden-2-yl)methylamino]propyl]-N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide ethanedioate (1:1).

To a solution of 2.45 g (0.0062 mol) ofN-(3-chloropropyl)-N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamidein 9 ml of N,N-dimethylformamide, under an argon atmosphere, are added1.71 g (0.0124 mol) of potassium carbonate and 1.03 g (0.0062 mol) ofpotassium iodide followed, after 5 min, by 1.14 g (0.0062 mol) ofN-methyl-2,3-dihydro-1H-inden2-amine hydrochloride and the mixture isheated at 85° C. for 4 h.

The mixture is allowed to cool, 50 ml of water and 50 ml of diethylether are added, the phases are separated and the aqueous phase isextracted with twice 50 ml of diethyl ether. The organic phases arecombined and washed with 50 ml of saturated aqueous sodium chloridesolution and dried over magnesium sulphate, and the solvent isevaporated. 3.04 g of oily product are obtained, which is purified bychromatography on a column of silica gel, eluting with a 97/3dichloromethane/methanol mixture. 0.930 g of pure base is obtained inthe form of an oil.

The oxalate is prepared in 2-propanol by adding 0.165 g (0.0018 mol) ofoxalic acid to 0.930 g (0.0018 mol) of base, and the product is isolatedand recrystallized from ethyl acetate. 0.64 g of oxalate is finallyobtained in the form of white crystals.

Melting point: 140°-141° C.

1.4.N-[3-[(2,3-Dihydro-1H-inden-2-yl)methylamino]propyl]-N-(3,4-dichlorophenyl)-5,6,7,8tetrahydronaphthalene-2-carboxamide (E)-2-butenedioate (1:1).

The fumarate is prepared in a mixture of 2-propanol and diisopropylether, by adding 1.05 g (0.009 mol) of fumaric acid to 4.58 g (0.009mol) of base. The salt is isolated and recrystallized from a mixture of2-propanol and diisopropyl ether. 4.28 g of fumarate are finallyobtained in the form of white crystals. Melting point: 160°-116° C.

EXAMPLE 2

(Compound No. 13)

N-(4-Chlorophenyl)-N-[3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl)propyl]-5,6,7,8-tetrahydronaphthalene-2-carboxamideethanedioate

2.1. N-(4-Chlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide.

To a suspension of 0.912 g (0.019 mol) of sodium hydride (50% in oil) in7 ml of dimethyl sulphoxide, under an argon atmosphere, is added onedrop of methanol. The mixture is left to stir for 10 min, and 1.40 g(0.011 mol) of 4-chlorobenzenamine are added. The mixture is stirred for15 min, 1.8 g (0.0095 mol) of methyl5,6,7,8-tetrahydro-naphthalene-2-carboxylate dissolved in 7 ml ofdimethyl sulphoxide are added dropwise and the stirring is continued atroom temperature for 3 h. 150 ml of water, 50 ml of diethyl ether and 50ml of ethyl acetate are added slowly, and the organic phase is separatedout, washed successively with 50 ml of water and 50 ml of saturatedaqueous sodium chloride solution, dried over magnesium sulphate andfiltered. The solvent is evaporated. The residue is crystallized fromdiethyl ether and 1.96 g of product are obtained, which is used as it isin the following step.

2.2.N-(4-Chlorophenyl)-N-(3-chloropropyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide.

To a solution of 1.92 g (0.0067 mol) ofN-(4-chlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide in 11 mlof N,N-dimethylformamide, under a nitrogen atmosphere, is added slowly,in small portions, 0.384 g (0.0080 mol) of sodium hydride as a 50%suspension in oil. The mixture is cooled to 0° C. 1.325 g (0.0084 mol)of 1-bromo-3-chloropropane are added dropwise. The mixture is allowed toreturn to room temperature and stirring is continued for 4 h.

The mixture is cooled, and 50 ml of water and 50 ml of diethyl ether areadded slowly. The phases are separated and the aqueous phase isextracted with 50 ml of diethyl ether. The organic phases are combinedand are washed successively with twice 50 ml of water, with 50 ml of 1Nhydrochloric acid, with twice 50 ml of water and with 50 ml of saturatedaqueous sodium chloride solution and dried over magnesium sulphate, andthe solvent is evaporated. 2.29 g of product are obtained, which productis used as it is in the following step.

2.3.N-(4-Chlorophenyl)-N-[3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl)propyl]-5,6,7,8-tetrahydronaphthalene-2-carboxamideethanedioate.

To a solution of 2.29 g (0.0063 mol) ofN-(4-chlorophenyl)-N-(3-chloropropyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamidein 9 ml of N,N-dimethylformamide, under an argon atmosphere, are added1.738 g (0.0126 mol) of potassium carbonate and 1.04 g (0.0063 mol) ofpotassium iodide followed, after 5 min, by 1.45 g (0.0063 mol) of6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride and themixture is heated at 85° C. for 4 h.

The mixture is allowed to cool, 50 ml of water and 50 ml of diethylether are added, the phases are separated and the aqueous phase isextracted with twice 50 ml of diethyl ether. The organic phases arecombined and washed with 50 ml of saturated aqueous sodium chloridesolution and dried over magnesium sulphate. The solvent is evaporated.3.1 g of oily product are obtained, which is purified by chromatographyon a column of silica gel, eluting with a 97/3 dichloromethane/methanolmixture. 1.33 g of pure base are obtained in the form of an oil.

The oxalate is prepared in 2-propanol by adding 0.230 g (0.0025 mol) ofoxalic acid to 1.32 g (0.0025 mol) of base, and the product is isolatedand recrystallized from 2-propanol. 1.0 g of oxalate is finally obtainedin the form of white crystals.

Melting point: 162°-163° C.

EXAMPLE 3

(Compound No. 17)

N-[3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl)propyl]-N-(4-methylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamideethanedioate

3.1. N-(4-Methylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide.

To a suspension of 0.912 g (0.019 mol) of sodium hydride (at a contentof 50% in oil) in 7 ml of dimethyl sulphoxide, under an argonatmosphere, is added one drop of methanol. The mixture is left to stirfor 10 min, and 1.177 g (0.011 mol) of 4-methylbenzenamine are added.The mixture is stirred for 15 min, 1.8 g (0.0095 mol ) of methyl5,6,7,8-tetrahydronaphthalene-2-carboxylate dissolved in 7 ml ofdimethyl sulphoxide are added dropwise, and the stirring is continued atroom temperature for 3 h. 150 ml of water, 50 ml of diethyl ether and 50ml of ethyl acetate are added slowly, and the organic phase isseparated, washed successively with 50 ml of water and 50 ml ofsaturated aqueous sodium chloride solution, dried over magnesiumsulphate and filtered. The solvent is evaporated. The residue iscrystallized from diethyl ether and 1.43 g of product are obtained,which is used as it is in the following step.

3.2.N-(3-Chloropropyl)-N-(4-methylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide.

To a solution of 1.4 g (0.0053 mol) ofN-(4-methylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide in 9 mlof N,N-dimethylformamide, under a nitrogen atmosphere, is added slowly,in small portions, 0.307 g (0.0064 mol) of sodium hydride as a 50%.suspension in oil. The mixture is cooled to 0° C., 1.048 g (0.0066 mol)of 1-bromo-3-chloropropane are added dropwise. The mixture is allowed toreturn to room temperature and stirring is continued for 4 h.

The mixture is cooled, 50 ml of water and 50 ml of diethyl ether areadded slowly, the phases are separated and the aqueous phase isextracted with 50 ml of diethyl ether. The organic phases are combinedand are washed successively with twice 50 ml of water, with 50 ml of 1Nhydrochloric acid, with twice 50 ml of water and with 50 ml of saturatedaqueous sodium chloride solution and dried over magnesium sulphate, andthe solvent is evaporated. 1.55 g of product are obtained, which is usedas it is in the following step.

3.3.N-[3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl)propyl]-N-(4-methylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamideethanedioate.

To a solution of 1.55 g (0.0045 mol) ofN-(3-chloropropyl)-N-(4-methylphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamidein 7 ml of N,N-dimethylformamide, under an argon atmosphere, are added1.24 g (0.009 mol) of potassium carbonate and 0.747 g (0.0045 mol) ofpotassium iodide followed, after 5 min, by 1.03 g (0.0045 mol) of6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride and themixture is heated at 85° C. for 4 h.

The mixture is allowed to cool, 50 ml of water and 50 ml of diethylether are added, the phases are separated and the aqueous phase isextracted with twice 50 ml of diethyl ether. The organic phases arecombined and washed with 50 ml of saturated aqueous sodium chloridesolution and dried over magnesium sulphate. The solvent is evaporated.2.07 g of oily are obtained, which product is purified by chromatographyon a column of silica gel, eluting with a 97/3 dichloromethane/methanolmixture. 0.920 g of pure base is obtained in the form of an oil.

The oxalate is prepared in 2-propanol by adding 0.162 g (0.0018 mol) ofoxalic acid to 0.9 g (0.0018 mol) of base, and the product is isolatedand recrystallized from 2-propanol. 0.797 g of oxalate is finallyobtained in the form of white crystals.

Melting point: 159°-160° C.

EXAMPLE 4

(Compound No. 26)

N-[4-(2-Methylpropoxy)phenyl]-N-[3-(1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-3-yl)propyl]-5,6,7,8-tetrahydronaphthalene-2-carboxamideethanedioate

4.1. N-[4-(2-Methylpropoxy)phenyl]acetamide.

To a solution of 23 g (0.15 mol) of N-(4-hydroxyphenyl)acetamide in 124ml of N,N-dimethylformamide are added 32.6 ml (0.3 mol ) of1-bromo-2-methylpropane and 31 g (0.225 mol) of potassium carbonate, andthe mixture is heated at 100° C. for 5 h. The mixture is cooled, thesolvent is evaporated, and the residue is taken up in 400 ml of diethylether and 200 ml of 1N sodium hydroxide. The organic phase is separatedand washed successively with three times 50 ml of 1N sodium hydroxide,with three times 100 ml of water and with 50 ml of saturated aqueoussodium chloride solution, dried over magnesium sulphate and filtered.The solvent is evaporated. 30.96 g of product are obtained, which isused as it is in the following step.

4.2.4-(2-Methylpropoxy)benzenamine.

To a solution of 30.35 g (0.146 mol) ofN-[4-(2-methylpropoxy)phenyl]acetamide in 157 ml of ethanol are added41.5 ml (0.309 mol) of 30% sodium hydroxide, and the mixture is heatedto reflux for 5 h. The solvent is evaporated and the residue is taken upin 400 ml of diethyl ether and 350 ml of water. The organic phase isseparated and washed successively with three times 100 ml of water andwith 50 ml of saturated aqueous sodium chloride solution, dried overmagnesium sulphate and filtered. The solvent is evaporated. 23.64 g ofproduct are obtained, which is purified by chromatography on a column ofsilica gel, eluting with a 7/3 cyclohexane/ethyl acetate mixture. 22.43g of product are obtained.

4.3.N-[4-(2-Methylpropoxy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-carboxamide.

To a suspension of 1.25 g (0.026 mol) of sodium hydride (at a content of50% in oil) in 10 ml of dimethyl sulphoxide, under an argon atmosphere,is added one drop of methanol, the mixture is left stirring for 10 minand 2.6 g (0.015 mol) of 4-(2-methylpropoxy)benzenamine are added. Themixture is stirred for 15 min, 2.5 g (0.013 mol) of methyl5,6,7,8-tetrahydronaphthalene-2-carboxylate dissolved in 10 ml ofdimethyl sulphoxide are added dropwise and the stirring is continued atroom temperature for 3 h. 200 ml of water, 100 ml of diethyl ether and100 ml of ethyl acetate are added slowly, the organic phase is separatedand is washed successively with 100 ml of water, with 100 ml of 1Nhydrochloric acid, with twice 50 ml of water and with 100 ml ofsaturated aqueous sodium chloride solution, dried over magnesiumsulphate and filtered. The solvent is evaporated.

The residue is crystallized from a mixture of diethyl ether and hexane,and 3.10 g of product are obtained, which is used as it is in thefollowing step.

4.4.N-(3-Chloropropyl)-N-[4-(2-methylpropoxy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-carboxamide.

To a solution of 2.5 g (0.008 mol) ofN-[4-(2-methylpropoxy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-carboxamidein 13 ml of N,N-dimethylformamide, under a nitrogen atmosphere, is addedslowly, in small portions, 0.5 g (0.010 mol) of sodium hydride as a 50%suspension in oil. The mixture is cooled to 0° C. 1.6 g (0.010 mol ) of1-bromo-3-chloropropane are added dropwise, the mixture is allowed toreturn to room temperature and stirring is continued for 4 h. Themixture is cooled. 100 ml of water and 100 ml of diethyl ether are addedslowly. The phases are separated and the aqueous phase is extracted with100 ml of diethyl ether. The organic phases are combined and are washedsuccessively with twice 50 ml of water, with 50 ml of 1N hydrochloricacid, with twice 50 ml of water and with 50 ml of saturated aqueoussodium chloride solution, and dried over magnesium sulphate. The solventis evaporated. 3.13 g of product are obtained, which is used as it is inthe following step.

4.5.N-[4-(2-Methylpropoxy)phenyl]-N-[3-(1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-3-yl)-propyl]-5,6,7,8-tetrahydronaphthalene-2-carboxamideethanedioate.

To a solution of 3.13 g (0.008 mol) ofN-(3-chloropropyl)-N-[4-(2-methylpropoxy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-carboxamidein 11 ml of N,N-dimethylformamide, under an argon atmosphere, are added2.21 g (0.016 mol) of potassium carbonate and 1.33 g (0.008 mol) ofpotassium iodide followed, after 5 min, by 1.67 g (0.008 mol) of1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indole hydrochloride and the mixtureis heated at 85° C. for 4 h. The mixture is allowed to cool, 100 ml ofwater and 100 ml of diethyl ether are added, the phases are separatedand the aqueous phase is extracted with twice 50 ml of diethyl ether.The organic phases are combined and washed with 100 ml of saturatedaqueous sodium chloride solution and dried over magnesium sulphate, andthe solvent is evaporated. 4.29 g of oily product are obtained, which ispurified by chromatography on a column of silica gel, eluting with a95/5 dichloromethane/methanol mixture. 1.63 g of pure base are obtainedin the form of an oil.

The oxalate is prepared in 2-propanol by adding 0.221 g (0.0025 mol) ofoxalic acid to 1.32 g (0.0025 mol) of base, and the product is isolatedand recrystallized from 2-propanol. 1.0 g of oxalate is finally isolatedin the form of white crystals.

Melting point: 121°-122° C.

EXAMPLE 5

(Compound No. 20)

N-(4-Methoxyphenyl)-N-[3-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-yl)propyl]-5,6,7,-tetarahydronaphthalene-2-carboxamideethanedioate

5.1. N-(4-Methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide.

To a suspension of 1.25 g (0.026 mol) of sodium hydride (at a content of50% in oil) in 10 ml of dimethyl sulphoxide, under an argon atmosphere,is added one drop of methanol, the mixture is left to stir for 10 min,and 1.92 g (0.015 mol) of 4-methoxybenzenamine are added. The mixture isleft to stir for 15 min, 2.5 g (0.013 mol) of methyl5,6,7,8-tetrahydronaphthalene-2-carboxylate dissolved in 10 ml ofdimethyl sulphoxide are added dropwise and the stirring is continued atroom temperature for 3 h. 200 ml of water, 100 ml of diethyl ether and100 ml of ethyl acetate are added slowly, and the organic phase isseparated and is washed successively with 100 ml of water, with 100 mlof 1N hydrochloric acid, with twice 50 ml of water and with 100 ml ofsaturated aqueous sodium chloride solution, dried over magnesiumsulphate and filtered, and the solvent is evaporated. 3.34 g of residueare obtained, which is crystallized from a mixture of diethyl ether andhexane. 2.69 g of product are obtained, which is used as it is in thefollowing step.

5.2.N-(3-Chloropropyl)-N-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide.

To a solution of 2.47 g (0.0088 mol) ofN-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide in 14 mlof N,N-dimethylformamide, under a nitrogen atmosphere, is added slowly,in small portions, 0.506 g (0.0105 mol) of sodium hydride as a 50%suspension in oil. The mixture is cooled to 0° C., 1.73 g (0.011 mol) of1-bromo-3-chloropropane are added dropwise. The mixture is allowed toreturn to room temperature and stirring is continued for 4 h. Themixture is cooled, 100 ml of water and 100 ml of diethyl ether are addedslowly, the phases are separated and the aqueous phase is extracted with100 ml of diethyl ether. The organic phases are combined and are washedsuccessively with twice 50 ml of water, with 50 ml of 1N hydrochloricacid, with twice 50 ml of water and with 50 ml of saturated aqueoussodium chloride solution, dried over magnesium sulphate and the solventis evaporated. 3.11 g of product are obtained, which is used as it is inthe following step.

5.3.N-(4-Methoxyphenyl)-N-[3-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-yl)propyl]-5,6,7,8-tetrahydronaphthalene-2-carboxamideethanedioate.

To a solution of 2.28 g (0.0064 mol) ofN-(3-chloropropyl)-N-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamidein 8 ml of N,N-dimethylformamide, under an argon atmosphere, are added1.76 g (0.0128 mol) of potassium carbonate and 1.06 g (0.0064 mol) ofpotassium iodide followed, after 5 min, by 1.1 g (0.0064 mol) of1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole hydrochloride and the mixtureis heated at 85° C. for 4 h. The mixture is allowed to cool. 100 ml ofwater and 100 ml of diethyl ether are added. The phases are separatedand the aqueous phase is extracted with twice 50 ml of diethyl ether.The organic phases are combined and washed with 100 ml of saturatedaqueous sodium chloride solution and dried over magnesium sulphate, andthe solvent is evaporated. 2.66 g of oily product are obtained, which ispurified by chromatography on a column of silica gel, eluting with a97/3 dichloromethane/methanol mixture. 0.930 g of pure base is obtainedin the form of an oil.

The oxalate is prepared in 2-propanol by adding 0.170 g (0.0019 mol) ofoxalic acid to 0.930 g (0.0019 mol) of base, and the product is isolatedand recrystallized from 2-propanol. 0.515 g of oxalate is finallyobtained in the form of white crystals.

Melting point: 245° C.

EXAMPLE 6

(Compound No. 28)

N-(4-Chlorophenyl)-N-[3-(2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)propyl]-5,6,7,8-tetrahydronaphthalene-2-carboxamideethanedioate

6.1. N-(4-Chlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide.

To a suspension of 0.912 g (0.019 mol) of sodium hydride (at a contentof 50% in oil) in 7 ml of dimethyl sulphoxide, under an argonatmosphere, is added one drop of methanol. The mixture is left to stirfor 10 min, and 1.40 g (0.011 mol) of 4-chlorobenzenamine are added. Themixture is left to stir for 15 min, 1.8 g (0.0095 mol) of methyl5,6,7,8-tetrahydro-naphthalene-2-carboxylate dissolved in 7 ml ofdimethyl sulphoxide are added dropwise and the stirring is continued atroom temperature for 3 h. 150 ml of water, 50 ml of diethyl ether and 50ml of ethyl acetate are added slowly, and the organic phase is separatedand washed successively with 50 ml of water and 50 ml of saturatedaqueous sodium chloride solution, dried over magnesium sulphate andfiltered. The solvent is evaporated. 2.5 g of residue are obtained,which is crystallized from diethyl ether. 1.96 g of product areobtained, which product is used as it is in the following step.

6.2.N-(4-Chlorophenyl)-N-(3-chloropropyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide.

To a solution of 1.92 g (0.0067 mol) ofN-(4-chlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide in 11 mlof N,N-dimethylformamide, under a nitrogen atmosphere, is added slowly,in small portions, 0.384 g (0.008 mol) of sodium hydride as a 50%suspension in oil. The mixture is cooled to 0° C. 1.325 g (0.0084 mol)of 1-bromo-3-chloropropane are added dropwise. The mixture is allowed toreturn to room temperature and stirring is continued for 4 h. Themixture is cooled, 50 ml of water and 50 ml of diethyl ether are addedslowly, the phases are separated and the aqueous phase is extracted with50 ml of diethyl ether. The organic phases are combined and washedsuccessively with twice 50 ml of water, with 50 ml of 1N hydrochloricacid, with twice 50 ml of water and with 50 ml of saturated aqueoussodium chloride solution, and dried over magnesium sulphate. The solventis evaporated. 2.29 g of product are obtained, which is used as it is inthe following step.

6.3.N-(4-Chlorophenyl)-N-[3-(2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)propyl]-5,6,7,8-tetrahydronaphthalene-2-carboxamideethanedioate.

To a solution of 2.5 g (0.0069 mol) ofN-(4-chlorophenyl)-N-(3-chloropropyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamidein 9 ml of N,N-dimethylformamide, under an argon atmosphere, are added1.9 g (0.0138 mol ) of potassium carbonate and 1.14 g (0.0069 mol ) ofpotassium iodide followed, after 5 min, by 1.26 g (0.0069 mol) of2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride and the mixture isheated at 85° C. for 4 h. The mixture is allowed to cool. 50 ml of waterand 50 ml of diethyl ether are added. The phases are separated and theaqueous phase is extracted with twice 50 ml of diethyl ether. Theorganic phases are combined and washed with 50 ml of saturated aqueoussodium chloride solution and dried over magnesium sulphate. The solventis evaporated. 3.04 g of oily product are obtained, which is purified bychromatography on a column of silica gel, eluting with a 97/3dichloromethane/methanol mixture. 1.18 g of pure base are obtained inthe form of an oil.

The oxalate is prepared in 2-propanol by adding 0.225 g (0.0025 mol) ofoxalic acid to 1.18 g (0.0025 mol) of base, and the product is isolatedand recrystallized from 2-propanol. 1.04 g of oxalate are finallyobtained in the form of white crystals.

Melting point: 180° C.

EXAMPLE 7

(Compound No. 27)

N-(4-Chlorophenyl)-N-[3-(4,5,6,7-tetrahydrothieno-[2,3-c]pyrid-6-yl)propyl]-5,6,7,8-tetrahydronaphthalene-2-carboxamideethanedioate (1:1)

To a solution of 2.37 g (0.0065 mol) ofN-(4-chlorophenyl)-N-(3-chloropropyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamidein 10 ml of N,N-dimethylformamide, under an argon atmosphere, are added2.69 g (0.0195 mol) of potassium carbonate and 1.1 g (0.0065 mol) ofpotassium iodide followed, after 5 min, by 1.49 g (0.0065 mol) of4,5,6,7-tetrahydrothieno[2,3-c]pyridine oxalate and the mixture isheated at 85° C. for 4 h. The mixture is allowed to cool. 50 ml of waterand 50 ml of diethyl ether are added. The phases are separated and theaqueous phase is extracted with twice 50 ml of diethyl ether. Theorganic phases are combined and washed with 50 ml of saturated aqueoussodium chloride solution and dried over magnesium sulphate. The solventis evaporated. 3.0 g of oily product are obtained, which is purified bychromatography on a column of silica gel, eluting with a 97/3dichloromethane/methanol mixture. 1.16 g of pure base are obtained inthe form of an oil.

The oxalate is prepared in 2-propanol by adding 0.26 g (0.0022 mol) ofoxalic acid to 1.16 g (0.0022 mol) of base, and the product is isolatedand recrystallized from 2-propanol. 1.09 g of oxalate are finallyobtained in the form of white crystals.

Melting point: 164°-165° C.

EXAMPLE 8

(Compound No. 31)

N-(4-Chlorophenyl)-N-[3-(2,3-dihydro-1H-isoindol-2-yl)propyl]-5,6,7,8-tetrahydronaphthalene-2-carboxamide(E)-2-butenedioate (1:1)

To a solution of 2.0 g (0.0055 mol) ofN-(4-chlorophenyl)-N-(3-chloropropyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamidein 10 ml of N,N-dimethylformamide, under an argon atmosphere, are added1.15 g (0.0083 mol) of potassium carbonate and 0.92 g (0.0055 mol) ofpotassium iodide followed, after 5 min, by 0.66 g (0.0055 mol) of2,3-dihydro-1H-isoindole. The mixture is heated at 85° C. for 4 h. Themixture is allowed to cool. 50 ml of water and 50 ml of diethyl etherare added. The phases are separated and the aqueous phase is extractedwith twice 50 ml of diethyl ether. The organic phases are combined andwashed with 50 ml of saturated aqueous sodium chloride solution anddried over magnesium sulphate. The solvent is evaporated. 2.8 g of oilyproduct are obtained, which product is purified by chromatography on acolumn of silica gel, eluting with a 97/3 dichloromethane/methanolmixture. 0.82 g of pure base is obtained in the form of an oil.

The fumarate is prepared in 2-propanol by adding 0.21 g (0.0018 mol) offumaric acid to 0.82 g (0.0018 mol) of base, and the product is isolatedand recrystallized from 2-propanol. 0.43 g of fumarate is finallyobtained in the form of white crystals.

Melting point: 141°-142° C.

EXAMPLE 9

(Compound No. 44)

(±)-N-[3-[(2,3-Dihydro-1H-inden-1-yl)methylamino]-propyl]-N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamideethanedioate (1:1)

To a solution of 3 g (0.0075 mol) ofN-(3-chloropropyl)-N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamidein 12 ml of N,N-dimethylformamide, under an argon atmosphere, are added2.07 g (0.015 mol) of potassium carbonate and 1.25 g (0.0075 mol) ofpotassium iodide followed, after stirring for 5 min, by 1.37 g (0.0075mol) of N-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride, and themixture is heated at 85° C. for 3h 30. The mixture is allowed to cool.50 ml of water are added and the brown precipitate is separated byfiltration, washed with water and dried. 3.58 g of product are obtained,which is purified by chromatography on a column of silica gel, elutingwith a 96/4 dichloromethane/methanol mixture. 1.12 g of pure base areobtained.

In order to prepare the oxalate, 0.73 g (0.0014 mol) of base and 0.13 g(0.0014 mol) of oxalic acid are dissolved in 10 ml of 2-propanol. Themixture is heated to reflux until the materials have dissolved, andcooled. The white precipitate is collected and recrystallized from2-propanol. After filtration and drying, 0.58 g of oxalate is finallyobtained.

Melting point: 142°-143° C.

EXAMPLE 10

(Compound No. 45)

(±)-N-[3-[(1,2,3,4-Tetrahydronaphthalen-1-yl)methylamino]propyl]-N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamideethanedioate (1:1)

To a solution of 3 g (0.0075 mol) ofN-(3-chloropropyl)-N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamidein 12 ml of N,N-dimethylformamide, under an argon atmosphere, are added2.07 g (0.015 mol) of potassium carbonate and 1.25 g (0.0075 mol) ofpotassium iodide followed, after stirring for 5 min, by 1.48 g (0.0075mol) of N-methyl-1,2,3,4-tetrahydronaphthalene-1-amine hydrochloride,and the mixture is heated at 85° C. for 3h 30. The mixture is allowed tocool. 50 ml of water are added and the yellow precipitate is separatedby filtration, washed with water and dried.

4.32 g of product are obtained, which is purified by chromatography on acolumn of silica gel, eluting with a 96/4 dichloromethane/methanolmixture. 1.34 g of pure base are obtained in the form of an oil.

In order to prepare the oxalate, the 1.34 g (0.0026 mol) of base and0.23 g (0.0026 mol) of oxalic acid are dissolved in 15 ml of 2-propanol.The mixture is heated to reflux until the materials have dissolved andthe solvent is evaporated. The residue is recrystallized from a largevolume of diisopropyl ether and the white precipitate is collected byfiltration and dried. 0.71 g of oxalate is finally obtained.

Melting point: 116°-117° C.

The Table which follows illustrates the chemical structures and thephysical properties of some compounds according to the invention. In the"Salt" column, "-" denotes a compound in the form of a base, "ox."denotes an oxalate or ethanedioate, "fum." denotes a fumarate or(E)-2-butenedioate, "cit." denotes a citrate or2-hydroxy-1,2,3-propanetricarboxylate, and "mes." denotes a mesotartrateor 2,3-dihydroxybutanedioate. The ratio indicated in parentheses is theacid:base molar ratio.

                                      TABLE                                       __________________________________________________________________________     ##STR5##                                                                     No.                                                                              R.sub.1 R'.sub.1 R".sub.1                                                              R.sub.3                                                                             R.sub.4    Salt  m.p. (°C.)                          __________________________________________________________________________     1                                                                                ##STR6##                                                                              CH.sub.3                                                                             ##STR7##  fum. (1.5:1)                                                                        132-133                                     2                                                                                ##STR8##                                                                              CH.sub.3                                                                             ##STR9##                                                                                 ##STR10##                                                                           ##STR11##                                  3                                                                                ##STR12##                                                                             CH.sub.3                                                                             ##STR13## fum. (1.5:1)                                                                        64-65                                       4                                                                                ##STR14##                                                                             CH.sub.2 CH.sub.2 CH.sub.3                                                           ##STR15## --    116-117                                     5                                                                                ##STR16##                                                                             CH.sub.2 CH.sub.2 CH.sub.3                                                           ##STR17## ox. (1.3:1)                                                                         73-74                                       6                                                                                ##STR18##                                                                             CH.sub.2 CH.sub.2 CH.sub.3                                                           ##STR19## fum. (1.5:1)                                                                        64-65                                       7                                                                                ##STR20##                                                                              ##STR21##       ox. (1:1)                                                                           185-186                                     8                                                                                ##STR22##                                                                              ##STR23##       fum. (1:1)                                                                          149-150                                     9                                                                                ##STR24##                                                                              ##STR25##       fum. (1:1)                                                                          159-160                                    10                                                                                ##STR26##                                                                              ##STR27##       fum. (1:1)                                                                          181-182                                    11                                                                                ##STR28##                                                                              ##STR29##       fum. (1:1)                                                                          154-155                                    12                                                                                ##STR30##                                                                              ##STR31##                                                                                      ##STR32##                                                                           ##STR33##                                 13                                                                                ##STR34##                                                                              ##STR35##       ox. (1.15:1)                                                                        162-163                                    14                                                                                ##STR36##                                                                              ##STR37##       ox. (1.15:1)                                                                        104-105                                    15                                                                                ##STR38##                                                                              ##STR39##       ox. (1.15:1)                                                                        145-146                                    16                                                                                ##STR40##                                                                              ##STR41##       ox. (1:1)                                                                           190-191                                    17                                                                                ##STR42##                                                                              ##STR43##       ox. (1.05:1)                                                                        159-160                                    18                                                                                ##STR44##                                                                              ##STR45##                                                                                      ##STR46##                                                                           ##STR47##                                 19                                                                                ##STR48##                                                                              ##STR49##       ox. (1.2:1)                                                                         234-235                                    20                                                                                ##STR50##                                                                              ##STR51##       ox. (1.1:1)                                                                         245                                        21                                                                                ##STR52##                                                                              ##STR53##       ox. (1.3:1)                                                                         118-119                                    22                                                                                ##STR54##                                                                              ##STR55##       ox. (1:1)                                                                           117-118                                    23                                                                                ##STR56##                                                                              ##STR57##       ox. (1:1)                                                                           144                                        24                                                                                ##STR58##                                                                              ##STR59##       ox. (1:1)                                                                           134-135                                    25                                                                                ##STR60##                                                                              ##STR61##       ox. (1.15:1)                                                                        134-135                                    26                                                                                ##STR62##                                                                              ##STR63##       ox. (1.35:1)                                                                        121-122                                    27                                                                                ##STR64##                                                                              ##STR65##       ox. (1:1)                                                                           164-165                                    28                                                                                ##STR66##                                                                              ##STR67##       ox. (1:1)                                                                           180                                        29                                                                                ##STR68##                                                                              ##STR69##       ox. (1.05:1)                                                                        202-203                                    30                                                                                ##STR70##                                                                              ##STR71##       ox. (1.15:1)                                                                        149-150                                    31                                                                                ##STR72##                                                                              ##STR73##       fum. (1:1)                                                                          141-142                                    32                                                                                ##STR74##                                                                             CH.sub.3                                                                             ##STR75## fum. (1:1)                                                                          159-161                                    33                                                                                ##STR76##                                                                             CH.sub.3                                                                             ##STR77## fum. (1:1)                                                                          119-121                                    34                                                                                ##STR78##                                                                             CH.sub.3                                                                             ##STR79## fum. (1:1)                                                                          177-179                                    35                                                                                ##STR80##                                                                             CH.sub.3                                                                             ##STR81## fum. (1:1)                                                                          158-160                                    36                                                                                ##STR82##                                                                             CH.sub.3                                                                             ##STR83## fum. (1:1)                                                                          162-164                                    37                                                                                ##STR84##                                                                             CH.sub.3                                                                             ##STR85## fum. (1:1)                                                                          169-171                                    38                                                                                ##STR86##                                                                             CH.sub.3                                                                             ##STR87## fum. (1:1)                                                                          157-159                                    39                                                                                ##STR88##                                                                             CH.sub.3                                                                             ##STR89## fum. (1:1)                                                                          153-155                                    40                                                                                ##STR90##                                                                             CH.sub.3                                                                             ##STR91## fum. (1:1)                                                                          157-159                                    41                                                                                ##STR92##                                                                             CH.sub.3                                                                             ##STR93## fum. (1:1)                                                                          146-148                                    42                                                                                ##STR94##                                                                             CH.sub.3                                                                             ##STR95## fum. (1:1)                                                                          155-157                                    43                                                                                ##STR96##                                                                             CH.sub.3                                                                             ##STR97## fum. (1:1)                                                                          159-161                                    44                                                                                ##STR98##                                                                             CH.sub.3                                                                             ##STR99## ox. (1:1)                                                                           142-143                                    45                                                                                ##STR100##                                                                            CH.sub.3                                                                             ##STR101##                                                                              ox. (1:1)                                                                           116-117                                    46                                                                                ##STR102##                                                                            CH.sub.3                                                                             ##STR103##                                                                              fum. (1:1)                                                                          201-203                                    47                                                                                ##STR104##                                                                            CH.sub.3                                                                             ##STR105##                                                                              ox. (1:1)                                                                           141-143                                    48                                                                                ##STR106##                                                                            CH.sub.3                                                                             ##STR107##                                                                              fum. (1:1)                                                                          87-89                                      49                                                                                ##STR108##                                                                            CH.sub.3                                                                             ##STR109##                                                                              fum. (1:1)                                                                          164-166                                    50                                                                                ##STR110##                                                                            CH.sub.3                                                                             ##STR111##                                                                              ox. (1.1:1)                                                                         144-146                                    51                                                                                ##STR112##                                                                            CH.sub.3                                                                             ##STR113##                                                                              ox. (1:1)                                                                           118-120                                    52                                                                                ##STR114##                                                                             ##STR115##      fum. (1:1)                                                                          158-159                                    __________________________________________________________________________

The compounds of the invention have been subjected to various testswhich have demonstrated their therapeutic utility.

Thus, they were subjected to the global cerebral ischemia test in mice.The ischemia caused by a cardiac arrest induced by rapid intravenousinjection of magnesium chloride. In this test, the "survival time" ismeasured, that is to say the interval between the moment of theinjection of magnesium chloride and the final observable respiratorymovement of each mouse. This final movement is considered as theultimate indication of central nervous system functioning. Under thetest conditions, respiratory arrest appears approximately 19 secondsafter the injection of magnesium chloride.

Male mice (Swiss OF1 IFFA CREDO) are studied in groups of 10. They aregiven food and drink ad libitum before the tests. The survival time ismeasured 10 minutes after intraperitoneal administration of thecompounds of the invention. The results are given in the form of thedifference between the survival time measured in a group of 10 micewhich received the compound and the survival time measured in a group of10 mice which received the vehicle liquid only. The ratios between thechanges in the survival time and the dosage of the compound are recordedgraphically as a semilogarithmic curve.

This curve makes it possible to calculate the "3 second effective dose"(ED₃ "), that is to say the dose (in mg/kg) which produces a 3-secondincrease in the survival time relative to the control group of 10untreated mice. A 3-second increase in the survival time is bothstatistically significant and reproducible. The ED₃ " of the compoundsof the invention range from 0.1 to 30 mg/kg when they are administeredvia the intraperitoneal route.

The compounds of the invention were also the subject of a study of thepotential-dependent ("voltage-dependent") barium currents by theso-called "patch-clamp" technique.

The barium currents flowing through the potential-dependent calciumchannels are measured on a preparation of new-born rat (Sprague-Dawley)cortex cells in culture (cultured for 6 to 10 days); in the case ofthese cells, these are composite currents which involve the L, N and Pchannels, as described in Soc. Neurosci. Abstr. (1989) 15 823.

The measuring chambers, 800 μl in volume, containing the cortex cells,are placed on the stage of an Olympus IMT-2™ inverted microscope and thecells are observed at a magnification of 400×. The chambers are perfusedcontinuously (4 to 5 ml/min) using a solution distributor device having9 inputs (dead volume <50 μl), the sole outlet of which, consisting of apolyethylene tube with a 500 μm opening, is placed less than 3 mm awayfrom the cell studied. This device has the advantage of allowing a rapidchange of solution on the cells studied.

The patch-clamp method used is described in Pfluegers Archives (1981)391 85-100. An Axopatch-1D™ amplifier connected to an AT 386-33 MHz typecomputer, using PCLAMP™ software from Axon Instruments™, is used forstimulation of the cells, acquisition of the data and analysis of theresults. In order to record the barium currents, borosilicate glasspipettes are brought close to the cells by means of a Narishige WR60™hydraulic micromanipulator. The tip of the pipettes is filled with thereference intracellular solution, the composition (in mM) of which is asfollows: CsCl (140), CaCl₂ (1), Na₂ TP (4), EGTA (11; pCa=8), Hepes(10), Tris-OH (pH =7.2).

Once the so-called "whole cell" configuration is obtained, the cell isperfused with a so-called TEA-Barium solution, the composition (in mM)of which is as follows: TEA-Cl (144), Batl₂ (5), MgCl₂ (2), CsCl (3),glucose (10), Hepes (10), Tris-OH (pH =7.4).

This solution makes it possible to measure the calcium current (similarto the barium current flowing through the potential-dependent calciumchannels) while at the same time being independent of the sodium andpotassium currents.

The global potential-dependent barium current is obtained by applicationof a depolarizing potential step with a duration of 250 ms, taking themembrane potential from -80 mV to 0 mV. The stimulation frequency is0.25 Hz.

The compounds of the invention are dissolved in the TEA-barium mediumand are applied once the amplitude of the barium current has stabilized.After obtaining a stable inhibitory effect, the cell is again perfusedwith the control TEA-barium solution in order to observe reversal of theeffect.

The strength of the effect obtained is compared to that of a 100 μMcadmium solution. Inhibition of the potential-dependent barium currentvaries as a function of the doses of compounds studied and, for the mostactive compounds, is of the order of 49% at a concentration of 1 μM andof 83% at a concentration of 10 μM.

The results of the tests carried out on the compounds of the inventionshow that, in vitro, they have neuronal calcium antagonist propertiesand, in vivo, they have neuroprotective and anti-ischaemic properties.

These results suggest that the compounds of the invention may be usedfor the treatment and prevention of cerebral disorders such as thosefollowing, for example, an ischaemic attack, a cardiac or respiratoryarrest, a cerebral embolism or thrombosis, for the treatment of cerebralsenility, dementia following multiple infarctions, senile dementia, forexample Alzheimer's disease or Pick's disease, for the treatment ofolivopontocerebellar atrophy and other neurodegenerative diseases suchas Huntington's chorea and amyotrophic lateral sclerosis, for thetreatment of cranial or spinal trauma, for the prevention of neuronaldamage following convulsive states, for the treatment of certaincancers, for the treatment of neurological damage caused by AIDS, andfor the prevention and treatment of diabetic retinopathies, degenerationof the optic nerve and retinopathies associated with glaucoma, and ingeneral for the treatment of any pathology associated with dysfunctionof the neuronal calcium homeostasis.

To this end, the compounds may be provided in any all pharmaceuticalform adapted for enteral or parenteral administration, in combinationwith suitable excipients, for example in the form of tablets,sugar-coated tablets, gelatin capsules, wafer capsules, suppositories,or drinkable or injectable solutions or suspensions, which are dosed toallow a daily administration of 1 to 1000 mg of active substance.

We claim:
 1. A compound, of the formula: ##STR116## in which R₁represents a hydrogen, halogen, methyl, or a C₁ -C₄ alkoxy,R'₁represents hydrogen or halogen; R"₁ represents hydrogen or methoxy andR₃ and R₄ together form, with the nitrogen atom to which they areattached, 1,2,3,4-tetrahydroisoquinol-2-yl, 6.7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl,5,8-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl,1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-yl,1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-3-yl,4,5,6,7-tetrahydrothieno[2,3-c]pyrid-6-yl, 2,3-dihydro-1H-isoindol-2-ylgroup, or 2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl, the respectiveformulae of which are as follows: ##STR117## provided that, when R₁ isalkoxy and each of R'₁ and R"₁ is hydrogen, R₃ and R₄ do not form, withthe nitrogen atom, an unsubstituted or substitutedtetrahydroisoquinol-2-yl groupin the form of a pure optical isomer or amixture thereof, and in the form of a base or an acid addition salt. 2.Compound according to claim 1, wherein R₁ represents halogen R'₁represents hydrogen or halogen R"₁ represents hydrogen, and R₃ and R₄together form, with the nitrogen atom to which they are attached,1,2,3,4-tetrahydroisoquinol-2-yl,6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl or5,8-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl.
 3. Pharmaceuticalcomposition useful for the treatment and prevention of cerebraldisorders comprising an effective account of a compound according toclaim 1, combined with excipient.